Project Summary/Abstract Developing new ways to treat pancreatic cancer is a significant challenge. Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and results in an estimated 37,000 deaths/year. Pancreatic cancer therapeutic options are limited to surgery and/or combinations of chemotherapy and radiation. Unfortunately, late-stage diagnosis of pancreatic cancer renders current therapies ineffective. The effectiveness of relatively new targeted treatments remains to be shown. There is an urgent major unmet medical need for the development of selective treatments for pancreatic cancer. Our new approach to pancreatic cancer is completely different and focuses on inhibition of a key molecular pathway. We have discovered and optimized a small molecule (i.e., 2) that selectively and potently inhibits a key molecular pathway. The overall Goal is to test this novel small molecule as an inhibitor to suppress pancreatic cancer progression by targeting a key signaling pathway. Compound 2 is non-toxic, pharmaceutically suitable for in vivo applications, and possesses a novel mechanism of action. Based on extensive in vitro and in vivo preliminary data, we have strong support that 2 will inhibit pancreatic cancer proliferation in vivo. The novelty of this project comes from the unique druggable target of the proposed anti-pancreatic cancer compound. The hypothesis that inhibition of a single molecular pathway can result in blocking three mechanisms of pancreatic cancer invasion including proliferation, migration and apoptosis and also block chemoresistance is novel. The proposed work can be readily accomplished because of the expertise of the team. The work will be divided into three straightforward Specific Aims. The Aims of the work include: 1) Show that lead compound 2 has the ability to potently inhibit proliferation and migration of cell models of pancreatic ductal adenocarcinomal (PDAC), 2) Do IND-enabling studies of 2 in preparation for an orthotopic xenograft study and 3) Do efficacy studies of 2 to show inhibition of growth and pathology of orthotopic PDAC cell xenografts in mice. The results will be summarized. The results obtained will afford fundamental information about a new approach to treat pancreatic cancer. The development of non-toxic inhibitors of molecular pathways crucial to pancreatic cancer represents a novel approach and addresses a major unmet medical need because the clinical utility of available approaches for treating human pancreatic cancer is limited. We hypothesize that lead compound 2 will inhibit pancreatic cancer proliferation in an in vivo orthotopic xenograft animal model of pancreatic cancer with minimal side effects and thus provide feasibility of a novel therapeutic strategy to treat pancreatic cancer.